Itching (pruritus) is a major clinical problem and one of the most disturbing symptoms of cutaneous and many systemic diseases. In normal skin, itch can be evoked by a variety of transient stimuli with no changes in cutaneous sensitivity. In contrast, under pathological conditions brought on, for example, by dermatitis, insect bites or experimentally by the application of a pruritic chemical such as histamine, a heightened pruritic state ("itchy skin") develops within and surrounding the affected skin. In itchy skin, normally pruritic stimuli elicit an enhanced itch (hyperknesis) and innocuous stimuli can evoke or enhance an ongoing itch or evoke an enhanced pain (alloknesis and hyperalgesia, respectively). There are few studies of the psychophysics of itch or of the somatic afferent pathways mediating itch. Similarly, there have been few psychophysical studies of the inhibition of itch or studies of the neural mechanisms mediating the inhibition. We propose psychophysical studies of itch, and its modulation by painful and other non-pruritic cutaneous stimuli, in normal skin and in chemically induced itchy skin. For both normal and itchy skin we will use a single adjective-labeled scale to compare the magnitude and time course of itch and pain sensations evoked by mechanical, heat and chemical stimuli. Differences in the magnitude and time course of itch and pain sensations evoked by each stimulus can be used in projects 2 and 3 to distinguish itch- from pain-coding sensory neurons. We will test the effects of non-pruritc conditioning stimuli (CS) in modulating itch in normal skin, itch in itchy skin and the development and persistence of itchy skin. We will test the hypothesis that there are two pruriceptive systems, one mediating itch, the other itchy skin and that each of these is under the inhibitory control of two different nociceptive systems - one operating within the area exposed to the CS and mediating pain or primary hyperalgesia, the other operating over a wider area and mediating secondary hyperalgesia and/or allodynia. The outcome of these studies will not only increase our understanding of itch and itchy skin. They will also provide novel information on endogenous mechanisms that inhibit itch and that may be appropriate targets for the development of drugs to control itching.